Eight separate projects related to outcomes of patients with rheumatic diseases are included in this report. The first project, Genetic determinants of ankylosing spondylitis severity, is a prospective observational study of 1200 subjects with ankylosing spondylitis (AS) that seeks to identify genetic determinants of AS susceptibility and severity. This project will test genotype-phenotype correlations in a large sample. Over 1000 subjects have been enrolled, and genetic testing and data analysis is underway. Radiographic data have been analyzed on 801 patients. Findings include 13 new genes associated with susceptibility to AS, gene-gene interaction between HLA-B27 and ERAP1 in risk of AS, impact of hip arthritis on physical functioning, lessening of association between radiographic damage and functional impairment with more prolonged AS, added value of using the Health Assessment Questionnaire to measure function in patients with peripheral joint arthritis, and association of ESR and CRP with axial impairments. Collaborators include Drs. J. Reveille, M. Brown, M. Weisman, J. Davis, T. Learch, and J. Malley. Ongoing work will test associations between several candidate genes involved in bone formation and regulation and the extent of radiographic damage. The second project, Progression of spinal fusion in ankylosing spondylitis, is a pilot study to develop a measure of spinal fusion in AS based on quantification of calcification of the lumbar intervertebral discs by computed tomography. Thirty-eight subjects have been enrolled, and 32 have completed follow-up scans at 1 and 2 years. Nine subjects completed studies testing the short-term reliability of measurements. Computer-based semi-automatic algorithms for determing syndesmophyte volume and height have been optimized to maximize reliabiilty, with less than 1% error on repeat scans. We have also developed this method to measure vertebral body height and disk height, which may be useful for precise measurement of vertebral fractures and disk disease Collaborators on this project are Drs. J. Flynn, L. Yao, Y. Yao, and S. Tan. The third project, Clinically important changes in rheumatoid arthritis, is a prospective observational study of clinically important changes in rheumatoid arthritis (RA) activity. Current criteria for improvement in RA have not emphasized the patients perspective. The goals of this project are to identify benchmarks of important improvement in pain, functioning, and global arthritis status in RA based on the self-assessment by patients of changes in their symptoms. A secondary goal is to examine the measurement properties of preference measures. To date, 262 patients have been enrolled. Initial results indicate patients are consistent in the degree of improvement necessary to be appreciated as an important change, and that clinical trial measures of improvement, such as the ACR20, are sensitive (but not specific) measures of improvement. The fourth project, Measurement of physical functioning, uses secondary analysis of clinical trial and observational data to understand what aspects of functioning are being measured in commonly used self-report instruments. We have found that performance measures are neither sensitive nor specific indicators of self-reported functional limitations. We have also found that, contrary to much previous literature, women and men have similar levels of self-reported functional limitations. In addition, we found no racial/ethnic differences in functional limitations after adjustment for measures of diseaseburden, although large differences by socioeconomic status remained despite adjustment for disease burden. The fifth project, outcomes in patients with rheumatoid arthritis, uses secondary data to examine risks of mortality, malignancy and cardiovascular disease between patients with RA and those without RA. We have found the perioperative risk of cardiovascular events and mortality not to be increased among persons with rheumatoid arthritis. We have begun to examine trends in rates of cardiovascular events over time. In contrast to the elevated rates reported recently, we have observed either no increase or relative reduction in rates of hospitalization for acute myocardial infarction among persons with rheumatoid arthritis treated in the 1970's and 1980's. We are currently exploring potential explanations for this apparent reversal in risk. We are planning a study of trends in risk of colorectal cancer and lymphoma in patients with rheumatoid arthritis, which may vary with changes in the treatments used over time. The sixth project, Treatment-related outcomes in rheumatoid arthritis, uses primary data to examine if particular disease-modifying medications are associated with higher- or lower-than- expected risks of mortality, using advanced statistical methods to account for differential prescribing of more serious medications to sicker patients. We have found that methotrexate is associated with a substantial survival benefit, not attributable to channeling or selective medication use. We are currently examining similar associations with low-dose prednisone use. We are also testing if differential access by patients of higher socioeconomic status to more effective anti-rheumatic medications over the past 25 years has resulted widening of socioeconomic disparites in health over time. The goals of the seventh project, Clinical epidemiology of systemic lupus erythematosus, are to investigate health disparities among patients with SLE, and to identify clinical features and health care practices that are associated with health outcomes. We are beginning systematic literature review of risk of end-stage renal disease in patients with lupus nephritis. The eighth project, Outcomes in Orthopedics, has a goal of investigating associations between processes and outcomes of orthopedic care. Initial studies have focused on time trends in the incidence of subtrochanteric fractures, using secondary data. Increases in incidence over time in the U.S. have paralleled increased use of bisphosphonate. Based on these observations, we have begun an observational study of 900 subjects to examine the association between chronic bisphosphonate use and subtrochanteric beaking, the radiographic precursor of subtrochanteric fracture. We have also examined differences in outcomes in fracture care related to use of either nails or plates, and have identified perioperative bleeding as a risk for operative site infection.